From 1633 until 1704, Franciscan monks established and operated a chain of missions and attempted to convert Florida Indians to Christianity. Apalachee missions also served as Spanish Florida's western defense network. In 1633, about 10,000 Indians lived in Apalachee Province: present-day Jefferson, Leon, and Wakulla counties.

There were eighteen Franciscan missions in Apalachee Province, though all did not exist at the same time. Each mission had two principal structures, a church and a convent, which were constructed of a wooden framework plastered with clay. The mission buildings were constructed by local Indian labor. A priest served each mission, and soldiers were garrisoned at the nearby fort of San Luis de Talimali.

In 1704, Colonel James Moore led a force of 1,500 whites and Yamassee Indians from the British colony of South Carolina into Apalachee Province. This army killed several priests, destroyed their missions, and enslaved many Indians. Few people remained in the area after Moore's raid, and Spain soon abandoned her province of Apalachee.